A. Field of the Invention
The invention relates generally to the use of staphylococcal and enterococcal glycoconjugate vaccines in preventing or treating bacterial infection in an immune-compromised individual.
B. Description of the Related Art
Staphylococci and Enterococci rarely cause systemic infections in otherwise healthy individuals, and therefore are considered opportunistic pathogens. Through various mechanisms, normal adult humans and animals with competent immune system attain an innate natural resistance to these bacterial infections. These include mucosal and epidermal barriers, in addition to possible immunological mechanisms. Interruption of these natural barriers as a result of injuries such as burns, traumas, or surgical procedures involving indwelling medical devices, increases the risk for staphylococcal and enterococcal infections. In addition, individuals with a compromised immune response such as cancer patients undergoing chemotherapy and radiation therapy, diabetes, AIDS, alcoholics, drug abuse patients, post organ transplantation patients and infants are at an increased risk for staphylococcal and enterococcal infections.
Staphylococci are commensal bacteria of the anterior nares, skin, and the gastrointestinal tract of humans. It is estimated that staphylococcal infections account for >50% of all hospital acquired infections. S. aureus alone is responsible for 15-25% of such infections and is surpassed only by S. epidermidis which accounts for 35% of these infections. Staphylococcal infections, especially those caused by S. aureus are associated with high morbidity and mortality.
Staphylococcus and enterococcus are a major cause of nosocomial and community-acquired infections, including bacteremia, metastatic abscesses, septic arthritis, endocarditis, osteomyelitis, and wound infections. For example, the bacteremia associated overall mortality for S. aureus is approximately 25 percent. A study of hospitalized patients in 1995 found that death rate, length of stay, and medical costs were twice as high for S. aureus-associated hospitalizations compared with other hospitalizations. S. aureus bacteremia is a prominent cause of morbidity and mortality in hemodialysis patients with an annual incidence of three to four percent. Contributing to the seriousness of S. aureus infections is the increasing percentage of isolates resistant to methicillin, and early reports of resistance to vancomycin. Hence, immunoprophylaxis against S. aureus is highly desired.
The capsular polysaccharides (CPS) of S. aureus are virulence factors in systemic infections caused by this opportunistic pathogen. S. aureus CPS confer invasiveness by inhibiting opsonphagocytic killing by polymorphonuclear neutrophils (PMN), similar to other encapsulated bacteria, such as Streptococcus pneumoniae. This enables the bacteria to persist in the blood, where they elaborate several different virulence factors, including toxins and extracellular enzymes. Of the 11 known types of S. aureus, Types 5 and 8 account for approximately 85 percent of all clinical isolates. Most of the remaining isolates carry a more-recently identified antigen known as Type 336. Antibodies to Types 5, 8 and 336 CPS induce type-specific opsonophagocytic killing by human PMNs in vitro, and confer protection in animal infection models.
Staphylococci have developed very sophisticated mechanisms for inducing diseases in humans, including both intracellular and extracellular factors. For instance, S. aureus possesses other surface antigens that facilitate its survival in the blood stream by helping the bacteria to evade phagocytic killing by the host leukocytes. These surface antigens include cell wall components such as teichoic acid, protein A, and capsular polysaccharides (CPS). Due in part to the versatility of these bacteria and their ability to produce extracellular products that enhance infectivity and pathogenesis, staphylococcal bacteremia and its complications such as endocarditis, septic arthritis, and osteomyelitis continue to be serious and frequently observed nosocomial infections.
Antibiotics such as penicillin have been used successfully against both staphylococcal and enterococcal infections in humans, but more recently the effectiveness of such antibiotics has been thwarted by the ability of bacteria to develop resistance. For example, shortly after the introduction of methicillin, a newer synthetic antibiotic, strains of methicillin-resistant S. aureus were isolated. Antibiotic resistance among staphylococcal isolates from nosocomial infections continues to increase in frequency, and resistant S. aureus strains continue to cause epidemics in hospitals in spite of developed preventive procedures and extensive research into bacterial epidemiology and antibiotic development. Enterococci resistant to vancomycin are now emerging, and methicillin-resistant S. aureus organisms with intermediate resistance to vancomycin have been identified in some centers. Cross transfer of resistance will eventually lead to the widespread development of organisms that are more difficult to eradicate.
The initial efficacy of antibiotics in treating and curing Staphylococcal infections drew attention away from immunological approaches for dealing with these infections. Although multiple antibiotic-resistant strains of S. aureus have emerged, other strategies such as vaccines have not been developed. In addition, passive immunization has been tested for use in immune-compromised individuals, such as neonates, who are at increased risk for contracting these bacterial infections. The data failed to support a solid conclusion in recommending the use of passive immunization in this population. Baker et al., New Engl. J. Med. 35:213-219 (1992); Fanaroff et al., New Engl. J. Med. 330:1107-1113 (1994). The use of active vaccination as an effective technique for protection of immune-compromised populations has not been realized as yet with any of the licensed vaccines. Vaccines that are immunogenic in healthy vaccinees are often found to be less or nonimmunogenic in immunocompromised patients, and thus to provide an insufficient level of protection. For example, the immune response of hemodialysis patients to hepatitis B vaccine was shown to be reduced to 50-80% of that seen in healthy vaccinees. Similarly, the immune response of elderly patients to this vaccine was reduced to 46%. Pirofski and Casadevall, Clin. Microbiol. Rev. 11:1-26 (1998).
Bacterial capsular polysaccharides are generally poor immunogens. Their immunogenicity in humans is known to be related to their molecular size and the age of the vaccinee. Infants below the age of two years, the elderly, and other immune-compromised patients are typically poor responders to CPS vaccines. While polysaccharide vaccines have been developed for some primary bacterial pathogens that induce acute diseases in normal individuals, namely, Streptococcus pneumoniae, Neisseria meningitidis and Hemophilus influenzae, none have been described specifically for treatment of opportunistic bacteria. Furthermore, when these vaccines were tested in immune-compromised individuals, a rapid decline in the immune response was observed, resulting in a lack of effective protection. In the case of S. pneumoniae, the vaccine tested included multiple strains, and worked in immunocompetent adults but not in immune-compromised individuals with poor immune response such as the elderly and AIDS patients. In the case of a S. aureus Type 5 conjugate vaccine, hemodialysis patients elicited lower maximal level amounts of antibodies compared to those elicited in healthy vaccinees, 180 ug/mil and 318 ug/ml, respectively. Moreover, a decline in antibody level occurred much more rapidly in dialysis patients than antibody levels in healthy vaccinees. After 6 months, antibody level in dialysis patients declined 39%, versus a 14% decline in healthy subjects. Welch et. al., J. Am. Soc. Neph. 7:247-253 (1996).
Live vaccines generally are more immunogenic, but present a concern when vaccinating immune-compromised patients. Although the viral and bacterial strains used in such vaccines are attenuated, some of the strains can revert back and cause disease. Immunization with a bacterial component vaccine especially is preferred for immune-compromised patients, such as chemotherapy patients, hemodialysis patients, infants, shock trauma patients, surgical patients, and others with reduced resistance or partially compromised immune systems.
Polysaccharide antigens normally generate a T-cell independent immune response and they induce humoral antibodies with no boost of the immune response observed upon reinjection. To generate a complete immune response, conjugation of polysaccharide to protein carriers can alter bacterial CPS antigens to make them T-cell dependent immunogens, thus increasing their immunogenicity and potentiating their use in infants and immune-compromised patients.
Immune-compromised individuals often are at high risk for bacterial infections, for example, from procedures such as catheterization. Given their poor immune response, exposure to an infectious strain of bacteria is likely to lead to a high level of infection. The fact that many bacterial strains have developed resistance to many or all current antibiotics increases the likelihood of a negative outcome when an immune-compromised individual does develop a bacterial infection. Therefore, it would be highly desirable to vaccinate immune-compromised against common clinically-significant bacterial strains. However, bacterial antigens such as the staphylococcal and enterococcal polysaccharide antigens are known to be poor immunogens. Their immunogenicity can be enhanced by conjugation to carrier proteins, but none of the currently available conjugate vaccines have ever been shown to be effective in immune-compromised patients, and it is widely accepted that these vaccines would be unable to produce an effective immune response in an immune-compromised population.